Investigating the Induction of Vaccine-Induced Th17 and Regulatory T Cells in Healthy,Mycobacterium bovis BCG-Immunized Adults Vaccinated with a New Tuberculosis Vaccine,MVA85A

Tuberculosis (TB) remains a threat to global health. While advances in diagnostics and treatment are crucial to the containment of the epidemic, it is likely that elimination of the disease can only be achieved through vaccination. Vaccine-induced protection from Mycobacterium tuberculosis is dependent, at least in part, on a robust Th1 response, yet little is known of the ability of TB vaccines to induce other T-cell subsets which may influence vaccine efficacy. Interleukin-17A (IL-17A) is a proinflammatory cytokine produced by Th17 cells which has been associated with both immune pathology and protection against infectious disease. Following vaccination with MVA85A, a viral vector vaccine aimed at enhancing immune responses to M. tuberculosis, antigen-specific IL-17A-producing T cells were induced in the peripheral blood of healthy volunteers. These T cells are detected later than gamma interferon (IFN-γ)-secreting T cells and are of a low magnitude. Preexisting immune responses to mycobacterial antigens were associated with higher CD4⁺ CD25^hi CD39⁺ T-cell levels in the periphery and a reduced capacity to produce IL-17A following immunization. These data highlight the intricate balance of effector and regulatory immune responses induced by vaccination and that preexisting immunity to mycobacterial antigens may affect the composition of vaccine-induced T-cell subsets.Tuberculosis (TB) remains a global health problem due to the emergence of drug-resistant strains of Mycobacterium tuberculosis, HIV-TB coinfection, and failure of the BCG vaccine to control adult pulmonary TB (9, 13). There is evidence that protection from M. tuberculosis is, at least in part, dependent on a robust Th1 response and the secretion of gamma interferon (IFN-γ) by antigen-specific T cells (1, 15, 22). Although IFN-γ alone is not sufficient for protection, in the absence of a better biomarker, early clinical trials of new TB vaccines use antigen-specific IFN-γ production as the primary gauge of vaccine-induced immune responses (16). In early clinical trials, modified vaccinia virus Ankara expressing antigen 85A from M. tuberculosis (MVA85A), a subunit vaccine designed to increase immune protection conferred by BCG, has been found to induce high levels of antigen-specific IFN-γ-secreting CD4⁺ T cells in individuals previously vaccinated with BCG (28, 29, 31).CD4⁺ T cells can differentiate into diverse effector cell subsets upon antigenic stimulation and the classical Th1/Th2 paradigm has now been expanded to include Th17 and T-regulatory (Treg) cells. Th17 cells are potent inflammatory cells which produce interleukin-17A (IL-17A) as their hallmark cytokine (17, 30). Th17 cells are mainly known for their role in mediating autoimmune pathology (19, 35) but are also thought to be involved in mediating protection against certain extracellular pathogens and fungi which are not effectively cleared by Th1- and Th2-type responses (12, 20). In contrast to Th17 cells, Treg cells comprise a regulatory cell subset of CD4⁺ T cells which act to suppress T-cell responses and are thereby thought to prevent pathology from chronic or excessive immune responses (21, 32, 33).Although a role has been defined for Th17 cells and Treg cells in other diseases, their role in TB remains unclear and even less is known about the effect of vaccination on these T-cell subsets.Clinical trials evaluating the safety and immunogenicity of MVA85A in BCG-vaccinated adults provide an opportunity to further investigate the induction and dynamics of vaccine-induced Th17 cells and Treg cells. Determining the effect of vaccination with MVA85A on these T-cell subsets is important, as protection from TB is likely to be dependent not only upon a Th1 response but also upon the balance between this effector response and the Th17 and Treg responses.